Project Summary: The long-term goal of our laboratory's research is to develop treatments to prevent irreversible damage to podocytes in children and adults, that would otherwise lead to End Stage Kidney Disease (ESKD). At present, irreversible kidney damage leads to dialysis and transplantation, situations that carry with them considerable morbidity and mortality and cost the health care system well over 20 billion dollars annually. We hypothesize that disease progression in glomeruli involves long term changes in gene expression in podocytes. The Wilms' tumor-1 gene (WT1) encodes one of the major transcription factors that regulates gene expression in podocytes. Our recent studies demonstrate that WT1 is a master regulator of gene expression in podocytes and appears to regulate the expression most key genes required to maintain normal podocyte function. WT1 also appears to regulate expression of several of the other transcription factors important in podocytes. WT1 levels decrease in many forms of glomerular disease. In this grant we propose to determine why Wt1 expression decreases in injured podocytes and to define at a genome level how the set of WT1 target genes changes in injured podocytes. We have also determined that a second transcription factor, FoxC2, often acts together with WT1 to regulate expression of key podocyte genes. We will also use a genome-wide approach to determine the set of FoxC2 target genes in podocytes and how these change after injury. These studies will identify genes and signaling pathways in podocytes whose activity increases or decreases after injury, that may serve as targets for pharmacological intervention to prevent irreversible podocyte injury or death and consequent glomerular disease and ESKD.